JPS63246365A - Alpha-halomethyl derivative of lactam of amino acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel halomethyl derivatives of lactams of amino acids.

[Configuration of the present invention] The compound of the present invention is represented by the following general formula (2).

H2 In the formula, Y is F2C11- or ClCH2-1n is an integer of 3 or 4.

Representative examples of pharmaceutically acceptable salts of compounds of the invention include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as methanesulfonic acid, salicylic acid, Maleic acid, malonic acid, tartaric acid, citric acid, cyclohexane sulfamic acid (cyclami
and inorganic or organic bases such as alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of group IIIA, For example, aluminum base,
Non-toxic salts prepared with organic amines such as primary, secondary or tertiary amines such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. This salt is produced by conventional methods.

A preferred compound of the present invention is a compound in which Y is F2CH-tearo.

[Effects of the present invention] The compound of general formula (2) is an inhibitor of the decarboxylase enzyme involved in polyamine production, and therefore, the compound is useful as a pharmacological agent.

Polyamines, especially putrescine, spermidine and spermine, are present in plant and animal tissues and in certain microorganisms. Although the precise physiological role of polyamines has not been clearly described, there is evidence to suggest that polyamines are involved in cell division and growth [H.G. Williams-Ashman, H.G. Wel
I 1a IIls Ashn+an) et al., The Italian Journal φ of φ Biochemicals Group, 5-3
2 (+976), A, Ra1na and J, Janne Medical Biochemistry 8.121-+47 (19
75) and D. H. Russell (D, H, Ru5)
sel l), Life Sciences, 1635~!
647 (+973)]. Polyamines are effective against certain microorganisms, such as E. coli, Enterobacter, Klebsiella M, and St.
aphylococcus aureus), C. cadaveris, Typhoid Fever II M (5aln+onel lat sophosa) and Haemophilus parainfluenza (Haemoph
illus parainfluenza) or associated with their growth stages. Polyamines are associated with both normal growth and rapid neoplastic growth, and an increase in polyamine synthesis and accumulation occurs following stimulation that causes cell proliferation. It is also known that patients with fetal, green, and rapidly growing tissues have higher levels of polyamines. It is known that there is a relationship between the activity of ornithine, S-7 denosylmethionine, arginine and lysine decarboxylase enzymes and polyamine production.

The biosynthesis of putrescine, spermidine and spermine are interrelated. Putrescine is a carboxyl group degradation product of ornithine catalyzed by ornithine decarboxylase.

Putrescine production can also occur by decomposing the carboxyl group of arginine to produce agmatine, which is then hydrolyzed to give putrescine and urea. Arginine is also involved in ornithine production through the action of the enzyme arginase. When methionine is activated by S-adenosylmethionine synthetase, S-adenosylmethionine is generated, which is decomposed by its carboxyl group, and then the propylamine moiety of the activated methionine is converted to putrescine to generate spermidine. Or the polyamine moiety is converted to spermidine to produce spermine. Therefore, putrescine acts as a precursor to spermidine and spermine, and an increase in putrescine synthesis is
It has been shown to have a significant regulatory effect on polyamine biosynthetic processes in that it has been shown to be the first sign that tissues are undergoing a regenerative growth process. Cadaverine, a carboxyl degradation product of lysine, has been shown to stimulate the activity of S-adenosylmethionine decarboxylase and has been shown to stimulate the activity of many microorganisms, such as H. influenzae (11, parainfluenza).
It is known that it is essential for the growth process of S. enza).

Compounds of general formula (1) are inhibitors of ornithine decarboxylase and lysine decarboxylase, as n changes from 3 to 4, respectively.

Compounds of general formula I are useful as anti-infective agents and are effective against microorganisms such as Escherichia coli, Enterobacter, Klebsiella,
Polyamines are used for the growth of Staphylococcus aureus, C. cadaveris, viruses such as H. influenzae, picornaviruses such as Mycobacterium encephalomyocarditis, H. simplex, herpes virus and arboviruses such as Semliki Forest virus. effective in controlling bacteria and viruses that depend on Compounds of general formula (1) are also useful in inhibiting certain rapid growth processes. For example, the compounds are used in the inhibition of spermatogenesis and embryonic development;
The compounds have therefore found use as male fertility inhibitors and abortifacients. The compounds are also useful in suppressing the immune response, so they are also used as immunosuppressants, and they are also used in the suppression of neoplastic growth, such as solid tumors, leukemias and lymphomas.

This compound is also useful as an inhibitor of scalp cell growth as evidenced by prostate enlargement and dandruff, and as an inhibitor of abnormal skin cell growth as evidenced by dry skin symptoms. The use of the compound of general formula (1) as an irreversible inhibitor of ornithine or S-adenosylmethionine decarboxylase enzymes in vivo is demonstrated below. An aqueous solution of the appropriate compound of formula (1) is administered orally or parenterally to male mice or mice. Animals were sacrificed 1 to 48 hours after compound administration, and the ventral lobe of the prostate was removed, homogenized, and
E, A, Pegg and H.
G. Williams-Ashman's Biochemical φ
Journal, 533-539 (1968) and J.J. and H.G. Williams-Ashman, Biochemical and Biophysical.
Research and communication, 222-228 (
The activity of ornithine or S-7 denosylmethionine decarpoxylase enzymes was determined as generally described by (1971).

[Manufacturing method] For the manufacturing method of the amino acid which is the starting material for manufacturing the compound of the present invention, see JP-A-54-19913.

Lactams of the compound of general formula (■) have the structure H2N (CH2
) n-c-coR19 formula vmH2 [where n and Y have the meanings defined in formula is methoxy, ethoxy, isopropoxy, butoxy or hexyloxy]; and more preferably Y is Cl
When CH2-, the amino acid is selected from the corresponding α-hydroxymethyl-substituted amino acid ester of the structure CII 208 82N(CH2)II CC0RI9 Formula IXH2 [where n and R+9 have the meanings defined in Formula ■■] The esters are dissolved 1/2 in a solvent such as a lower alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol, water, dimethylformamide, dimethyl sulfoxide, hexamethylphosphortriamide or mixtures of these solvents.
A suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, optionally under a nitrogen atmosphere, at a temperature of about 0'' to 120°C for a period of time to 24 hours. potassium tert-butoxide,
treatment with sodium amide or an organic amine such as a trialkylamine, such as triethylamine, after which Y
IC) 12- in a solvent such as formamide, dimethylformamide or dimethylacetamide for 12 to 36 hours about 406~! It is produced by treatment with chlorinating agents such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride at 20°C.

The compound of general formula (2) can be prepared from the corresponding amino acid using methods generally known in the art.
It is obtained by treating CI gas with a suitable saturated alcohol, such as methanol, ethanol, isopropyl alcohol, n-butanol or n-heptatool.

General ceremony! Compound X is synthesized by synthesis LEL7.1.79
By the general method described in 2, one equivalent of ornithine or lysine is treated with two equivalents of benzoyl chloride, followed by two equivalents of a base, e.g. sodium hydroxide, to produce a bisamide, which is Treatment with an acid anhydride, such as acetic anhydride, at 90°C for about 1/2 hour, followed by aqueous formaldehyde and pyridine at about 25°C for about 8-24 hours, followed by water treatment to produce oxo Dioxane is obtained by treating it with a catalytic amount of sodium methoxide in methanol, followed by neutralization and treatment with an acid, such as hydrochloric acid, at about 120 DEG C. for about 2 to 24 hours.

Each optical isomer of the amino acid corresponding to the lactam of the compound of general formula (i17 (+971)
Obtained by the method. Other resolving reagents can also be used, such as (+) camphor-10-sulfonic acid. Similarly, Z
is β-methylthioethyl, R is hydrogen, and R1 is hydroxy. Reagent e.g. (+) Shonou-10
-obtained using sulfonic acid.

Example: A solution of methyl-2-difluoromethyl-2,5-diamino-pentanoate-dihydrochloride (2,7 g) in dry methanol (30 ml) was added under nitrogen to a solution containing methyl-2-difluoromethyl-2,5-diamino-pentanoate-dihydrochloride (2,7 g) in methanol (30 ml). An equivalent amount of sodium methylate (0.46 g of sodium in 201 methanol) was added. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was evaporated under reduced pressure. Extraction of the residue with ether yields the crude 3-amino-3-
Difluoromethyl-2-piperidone is obtained, which is converted to C
by crystallization from HCl3/pentane (melting point 149°C) or by distillation (boiling point 135°C/0.05 mm
Hg) Purified.

To a solution of (±)binaphthyl phosphate (8NPA) (1,27 g) in hot ethanol (50+wl) was added (±)3-amino-3-difluoromethyl-2-piperidone (0, A solution of 546 mg) was added. On cooling, the crystals separated. The reaction mixture was then left at 4°C overnight. When the precipitate was filtered and washed with ethanol and diethyl ether, 0.54 g of (-)
Binaphthyl phosphate ([α colo = -409°c = 0.
3.MeOH melting point: 300°C) was obtained. Recrystallization of the mother liquor yielded 0.15 g of (-)binaphthyl phosphate. When the filtrate is concentrated, 1.1. g of sticky material was obtained, which was treated with 3M HCl for 3 hours at room temperature. The (-)8NPA was filtered off and the filtrate was concentrated under reduced pressure. When the residue is recrystallized in ethanol, (+)
3-Amino-3-difluoromethyl-2-piperidone-
Hydrochloride (160 mg) ([α] mouth=+18”6.
c = 1, MeOH) (M point 238°C) was obtained.

When treated under the same conditions, (-)BNPA salt (436 m
g) is (-)3-amino-3-difluoromethyl-2-
Piperidone-hydrochloride (f37mg) was given, which was recrystallized in ethanol (67mg) ([α]
o=-19″′, c=1.02, MeOtl: melting point=2
decomposed at 40°C).

(Reference example) (-)3-difluoromethyl-3-amino-2-piperidone hydrochloride (60mg) 6M) ICL (4ml)
The mixture was heated under reflux for 12 hours. After contracting by 1 under reduced pressure,
Dissolve the residue in water and adjust the pH of the solution to NEt3.
It was adjusted to 4.5 using a solution of The solution was then condensed under reduced pressure and the residue was extracted several times with chloroform and then lI
Recrystallization from 20/EtOH gives (+)2-difluoromethyl-2,5-diaminopentanoic acid-hydrochloride (
54n+g) ([al [+=+6, c=0.48
; MeOtl ; melting point ≧240°C) was obtained. By the same treatment, (+)3-difluoromethyl-3-amino-2-piperidone hydrochloride (96 mg) was converted to (-)2-
Difluoromethyl-2.5-diaminopentanoic acid hydrochloride (56 mg) was given. ([(! 10 = -10
', c = 0.7, MeOH, melting point ≧244") (Reference example) .5X 10-2 mol) to 751
1 in anhydrous methanol and the solution was saturated with dry hydrogen chloride. The homogeneous solution was then heated under reflux for 48 hours. The reaction mixture was uniformly saturated with dry hydrogen chloride. The solution was evaporated under reduced pressure and a hygroscopic residue (6,
2g) was dried under high vacuum and identified by nuclear magnetic resonance as the dihydrochloride salt of 2-hydroxymethyl-2,5-diaminopentanoic acid methyl ester. The ester (s, 2 g) was dissolved in room ml of anhydrous methanol and 175 ml of a methanolic solution of sodium methylate (t, tsg of Na i.e. 5 X 10-2
mol) was added. The reaction mixture was stirred at room temperature for 24 hours under nitrogen. The solvent was evaporated under reduced pressure and the residue was extracted several times with hot chloroform to give an analytical solution of pure 3-hydroxymethyl-3-amino-2-piperidone (2.9 g) in a yield of 81 g. melting point 145
℃.

3-Hydroxymethyl-3 in anhydrous dimethylformamide (50 ml)
A solution containing 1 equivalent of thionyl chloride (3J
ml) was added. The reaction mixture was stirred at 80°C under nitrogen. After 24 hours, 1 equivalent of thionyl chloride (3.6 ml) was added to the colander and stirring was continued for 2 hours. The solvent was then stripped under reduced pressure. The semi-solid residue was triturated with chloroform (2X 30ml) to give 2
．． Pure 3-amino-3-chloromethyl-2-piperidone hydrochloride was obtained with 18 crystalline analytical solutions. Melting point 23
0℃.

Applicant: Merrell Dow Pharmaceuticals, Inc.

Claims (1)

[Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y is F_2CH- or ClCH_2-, and n
is an integer 3 or 4], and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein Y is F_2CH-. 3. Compounds that are lactams of amino acids of the formula ▲ Numerical formulas, chemical formulas, tables, etc. [wherein Y is F_2CH or ClCH_2-, and n is an integer 3 or 4] or pharmaceutically acceptable salts thereof In the production method, the corresponding amino acid ester is dissolved in a suitable solvent by about 1/2 to 2
treatment with base at 0° to 120° C. for 4 hours, optionally under a nitrogen atmosphere, and when Y is ClCH_2- in a suitable solvent for about 1 hour.
A process comprising an additional step of treatment with a chlorinating agent at about 400-120<0>C for 2-36 hours.